This article requires a subscription to view the full text. If you have a subscription you may use the login form below to view the article. Access to this article can also be purchased.

Significance

Antibodies blocking inhibitory checkpoints on T cells have been a major advance in cancer treatment. However, agonistic antibodies have had less success due to toxicity concerns. Harnessing the knowledge that agonistic antibodies require the inhibitory Fc receptor (FcR), we engineered a CD40 antibody with improved in vivo activity. Because current models fail to recapitulate important dose-limiting toxicities in patients, we developed a mouse model carrying human CD40 and FcRs. This model mirrors human toxicities and allowed for the development of an in situ vaccination approach leading to durable tumor control. These results support the rational design of immune modulating antibodies as well as stress the importance, and possible reconsiderations needed, for optimal preclinical models allowing parallel efficacy and toxicity analyses.

Abstract

Immune stimulation has emerged as a promising approach to the treatment of neoplastic diseases. Currently approved therapeutics, such as anti-CTLA4 and anti-PD1, are primarily aimed at blocking inhibitory signaling by immune cells. An alternative and potentially synergistic approach would involve activation of immune pathways by agonism of stimulatory receptors, such as CD40. Agonistic antibodies, while promising in principle, have encountered significant barriers in clinical trials limited by the systemic toxicity of such approaches. Using a mouse model humanized for both Fc receptors and CD40, we previously demonstrated enhanced antitumor activity with an Fc-modified antibody. We now demonstrate that this model recapitulates the platelet and hepatic toxicities seen with anti-CD40 antibodies in patients, providing a predictive measure of the dose-limiting activity of this approach. We further show that such toxicity can be circumvented and durable systemic antitumor immunity achieved by intratumoral delivery of an Fc-engineered anti-CD40 agonistic antibody.

Blood-sucking sand flies from disparate global regions have a predilection for feeding on the marijuana plant (Cannabis sativa), and the findings hint at a potential avenue for controlling sand flies, which can transmit leishmaniasis.